Cancer Discovery,
Год журнала:
2020,
Номер
10(8), С. 1129 - 1139
Опубликована: Май 19, 2020
Most
patients
with
KRAS
G12C-mutant
non-small
cell
lung
cancer
(NSCLC)
experience
clinical
benefit
from
selective
KRASG12C
inhibition,
whereas
colorectal
bearing
the
same
mutation
rarely
respond.
To
investigate
cause
of
limited
efficacy
inhibitors
in
cancer,
we
examined
effects
AMG510
G12C
lines.
Unlike
NSCLC
lines,
models
have
high
basal
receptor
tyrosine
kinase
(RTK)
activation
and
are
responsive
to
growth
factor
stimulation.
In
inhibition
induces
higher
phospho-ERK
rebound
than
cells.
Although
upstream
several
RTKs
interferes
blockade,
identify
EGFR
signaling
as
dominant
mechanism
resistance
inhibitors.
The
combinatorial
targeting
is
highly
effective
cells
patient-derived
organoids
xenografts,
suggesting
a
novel
therapeutic
strategy
treat
cancer.
SIGNIFICANCE:
lineage-specific.
RTK
dependency
kinetics
responsible
for
sensitivity
or
should
be
concomitantly
inhibited
overcome
blockade
tumors.See
related
commentary
by
Koleilat
Kwong,
p.
1094.This
article
highlighted
This
Issue
feature,
1079.
Protein & Cell,
Год журнала:
2020,
Номер
12(8), С. 599 - 620
Опубликована: Окт. 1, 2020
Abstract
The
cystine/glutamate
antiporter
SLC7A11
(also
commonly
known
as
xCT)
functions
to
import
cystine
for
glutathione
biosynthesis
and
antioxidant
defense
is
overexpressed
in
multiple
human
cancers.
Recent
studies
revealed
that
overexpression
promotes
tumor
growth
partly
through
suppressing
ferroptosis,
a
form
of
regulated
cell
death
induced
by
excessive
lipid
peroxidation.
However,
cancer
cells
with
high
expression
(SLC7A11
)
also
have
endure
the
significant
cost
associated
SLC7A11-mediated
metabolic
reprogramming,
leading
glucose-
glutamine-dependency
cells,
which
presents
potential
vulnerabilities
therapeutic
targeting
cancer.
In
this
review,
we
summarize
diverse
regulatory
mechanisms
cancer,
discuss
ferroptosis-dependent
-independent
promoting
development,
explore
mechanistic
basis
SLC7A11-induced
nutrient
dependency
conceptualize
strategies
target
treatment.
This
review
will
provide
foundation
further
understanding
dependency,
biology
developing
novel
effective
therapies.
New England Journal of Medicine,
Год журнала:
2021,
Номер
384(25), С. 2371 - 2381
Опубликована: Июнь 4, 2021
Sotorasib
showed
anticancer
activity
in
patients
with
KRAS
p.G12C–mutated
advanced
solid
tumors
a
phase
1
study,
and
particularly
promising
was
observed
subgroup
of
non–small-cell
lung
cancer
(NSCLC).
Cancer Research,
Год журнала:
2020,
Номер
80(14), С. 2969 - 2974
Опубликована: Март 24, 2020
Ras
is
frequently
mutated
in
cancer,
however,
there
a
lack
of
consensus
the
literature
regarding
cancer
mutation
frequency
Ras,
with
quoted
values
varying
from
10%-30%.
This
variability
at
least
part
due
to
selective
aggregation
data
different
databases
and
dominant
influence
particular
types
isoforms
within
these
datasets.
To
provide
more
definitive
figure
for
we
cross-referenced
all
major
publicly
accessible
determine
reliable
each
isoform
types.
These
percentages
were
then
applied
current
U.S.
incidence
statistics
estimate
number
new
patients
year
that
have
Ras-mutant
cancers.
We
find
approximately
19%
harbor
mutations,
equivalent
3.4
million
cases
per
worldwide.
discuss
mutation-specific
trends
evident
datasets
are
relevant
Ras-targeted
therapies.
Signal Transduction and Targeted Therapy,
Год журнала:
2021,
Номер
6(1)
Опубликована: Ноя. 15, 2021
Abstract
Cancer
is
the
leading
cause
of
death
worldwide,
and
its
treatment
outcomes
have
been
dramatically
revolutionised
by
targeted
therapies.
As
most
frequently
mutated
oncogene,
Kirsten
rat
sarcoma
viral
oncogene
homologue
(KRAS)
has
attracted
substantial
attention.
The
understanding
KRAS
constantly
being
updated
numerous
studies
on
in
initiation
progression
cancer
diseases.
However,
deemed
a
challenging
therapeutic
target,
even
“undruggable”,
after
drug-targeting
efforts
over
past
four
decades.
Recently,
there
surprising
advances
directly
drugs
for
KRAS,
especially
(G12C)
inhibitors,
such
as
AMG510
(sotorasib)
MRTX849
(adagrasib),
which
obtained
encouraging
results
clinical
trials.
Excitingly,
was
first
to
be
approved
use
this
year.
This
review
summarises
recent
fundamental
aspects
relationship
between
mutations
tumour
immune
evasion,
new
progress
targeting
particularly
(G12C).
Moreover,
possible
mechanisms
resistance
inhibitors
combination
therapies
are
summarised,
with
view
providing
best
regimen
individualised
achieving
truly
precise
treatment.
Journal of Medicinal Chemistry,
Год журнала:
2019,
Номер
63(1), С. 52 - 65
Опубликована: Дек. 10, 2019
KRASG12C
has
emerged
as
a
promising
target
in
the
treatment
of
solid
tumors.
Covalent
inhibitors
targeting
mutant
cysteine-12
residue
have
been
shown
to
disrupt
signaling
by
this
long-“undruggable”
target;
however
clinically
viable
yet
be
identified.
Here,
we
report
efforts
exploit
cryptic
pocket
(H95/Y96/Q99)
identified
identify
suitable
for
clinical
development.
Structure-based
design
leading
identification
novel
quinazolinone
scaffold
are
described,
along
with
optimization
that
overcame
configurational
stability
issue
arising
from
restricted
rotation
about
an
axially
chiral
biaryl
bond.
Biopharmaceutical
resulting
leads
culminated
AMG
510,
highly
potent,
selective,
and
well-tolerated
inhibitor
currently
phase
I
trials
(NCT03600883).
